Anti-cancer and anti-microbial oxazolidinones

ABSTRACT

Disclosed herein are various novel oxazolidinone, imidazolidinone, and thiazolidinone analogs and methods of treating cancer and/or microbial infection using these analogs. Particular 4-oxazolidinone compounds are shown to have anti-cancer and anti-microbial activity.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/358,961, filed Feb. 21, 2006, which claims the benefit of U.S.Provisional Application No. 60/655,605, filed on Feb. 22, 2005, both ofwhich are incorporated herein by reference in their entirety.

BACKGROUND

1. Field of the Invention

The present invention relates to the fields of chemistry and medicine.More particularly, the present invention relates to certainoxazolidinone, imidazolidinone, and thiazolidonone analogs and use ofthose analogs in anti-cancer and anti-microbial pharmaceuticals.

2. Description of the Related Art

Cancer is a leading cause of death in the United States. Despitesignificant efforts to find new approaches for treating cancer, theprimary treatment options remain surgery, chemotherapy and radiationtherapy, either alone or in combination. Surgery and radiation therapy,however, are generally useful only for fairly defined types of cancer,and are of limited use for treating patients with disseminated disease.Chemotherapy is the method that is generally useful in treating patientswith metastatic cancer or diffuse cancers such as leukemias. Althoughchemotherapy can provide a therapeutic benefit, it often fails to resultin cure of the disease due to the patient's cancer cells becomingresistant to the chemotherapeutic agent. Due, in part, to the likelihoodof cancer cells becoming resistant to a chemotherapeutic agent, suchagents are commonly used in combination to treat patients.

Similarly, infectious diseases caused, for example, by bacteria arebecoming increasingly difficult to treat and cure. For example, more andmore microorganisms, such as bacteria, are developing resistance tocurrent antibiotics and chemotherapeutic agents. Examples of suchbacteria include both gram positive and gram negative bacteria,including Staphylococcus, Streptococcus, Mycobacterium, Enterococcus,Corynebacterium, Borrelia, Bacillus, Chlamidia, Mycoplasma, and thelike. Examples of Fungi include Aspergillus, Candida, Trichoderma, andthe like. Examples of protozoa include Plasmodium and Acanthamoeba.

Therefore, a need exists for additional chemotherapeutics andantimicrobial agents to treat cancer and infectious disease. Acontinuing effort is being made by individual investigators, academiaand companies to identify new, potentially useful chemotherapeutic andantimicrobial agents.

Marine-derived natural products are a rich source of potential newanti-cancer agents and anti-microbial agents. The oceans are massivelycomplex and house a diverse assemblage of microbes that occur inenvironments of extreme variations in pressure, salinity, andtemperature. Marine microorganisms have therefore developed uniquemetabolic and physiological capabilities that not only ensure survivalin extreme and varied habitats, but also offer the potential to producemetabolites that would not be observed from terrestrial microorganisms(Okami, Y. 1993 J Mar Biotechnol 1:59). Representative structuralclasses of such metabolites include terpenes, peptides, polyketides, andcompounds with mixed biosynthetic origins. Many of these molecules havedemonstrable anti-tumor, anti-bacterial, anti-fungal, anti-inflammatoryor immunosuppressive activities (Bull, A. T. et al. 2000 Microbiol MolBiol Rev 64:573; Cragg, G. M. & D. J. Newman 2002 Trends Pharmacol Sci23:404; Kerr, R. G. & S. S. Kerr 1999 Exp Opin Ther Patents 9:1207;Frenz, J. L., Kohl, A. C. & R. G. Kerr 2004 Exp Opin Ther Patents 14:17;Moore, B. S 1999 Nat Prod Rep 16:653; Faulkner, D. J. 2001 Nat Prod Rep18:1; Mayer, A. M. & V. K. Lehmann 2001 Anticancer Res 21:2489),validating the utility of this source for isolating invaluabletherapeutic agents. Further, the isolation of novel anti-cancer andanti-microbial agents that represent alternative mechanistic classes tothose currently on the market will help to address resistance concerns,including any mechanism-based resistance that may have been engineeredinto pathogens for bioterrorism purposes.

SUMMARY OF CERTAIN EMBODIMENTS

One aspect of the invention is a compound having the structure offormula I or Ia:

and pharmaceutically acceptable salts or prodrugs thereof, wherein:

R¹ and R² are separately selected, wherein one of R¹ and R² is amolecular fragment having the structure of formula (II),

Z is selected from the group consisting of O, S, and NR⁵;

R¹ and R⁷ are separately selected from the group consisting of hydrogen;halogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁-C₂₄ alkyl,C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; and the remainingsubstituent of R¹ and R² is selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl;

R³ is ═O;

R^(1′) and R^(2′) are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

Y is selected from the group consisting of O, S, and NR⁵;

R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl, or areseparately absent, provided that R⁴ is not absent in a compound offormula Ia;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

Another aspect of the invention is a compound having the structure offormula III or IIIa:

and pharmaceutically acceptable salts or prodrugs thereof, wherein:

Y is selected from the group consisting of O, S, and NR⁵;

R², R⁶, and R⁷ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl;

R^(2′) is selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; or isabsent;

R⁴ and R⁵ are separately selected from the group consisting of hydrogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl or are separatelyabsent, provided that R⁴ is not absent in a compound of formula IIIa;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

Another aspect of the invention is a compound having the structure offormula IV or IVa:

and pharmaceutically acceptable salts or prodrugs thereof, wherein:

R², R⁶, and R⁷ are separately selected from the group consisting ofmono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl;

R^(2′) is selected from the group consisting of hydrogen andmono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl;

R⁴ is selected from the group consisting of hydrogen, straight- orbranched-chain C₁₋₆ alkyl, straight- or branched-chain C₂₋₆ alkenyl, andstraight- or branched-chain C₂₋₆ alkynyl, or is absent, provided that R⁴is not absent in a compound of formula IVa;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bondwith the proviso that such bonds in the compound of formula IV may notboth be double bonds; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

Another aspect of the invention is a compound having the structure offormula V or Va:

and pharmaceutically acceptable salts or prodrugs thereof, wherein:

Y is selected from the group consisting of O and NR⁵;

Z is selected from the group consisting of O, S, and NR⁵;

R², R⁶, and R⁷ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy;nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;

R^(2′) is selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl; or is absent;

R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl or are separatelyabsent, provided that R⁴ is not absent in a compound of formula Va;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

R⁶ and R⁸ are optionally bound together to form an optionallysubstituted ring;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

Another aspect of the invention is a compound having the structure offormula V or Va:

and pharmaceutically acceptable salts or prodrugs thereof, wherein:

Y is selected from the group consisting of O, S, and NR⁵;

Z is selected from the group consisting of O, S, and NR⁵;

R², R⁶, and R⁷ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy;nitro; azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl;carboxy; cyano; and halogenated alkyl including polyhalogenated alkyl;

R^(2′) is selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl; or is absent;

R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl or are separatelyabsent, provided that R⁴ is not absent in a compound of formula Va;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

R⁶ and R⁸ are optionally bound together to form an optionallysubstituted ring, provided that if R⁶ and R⁸ together form an aryl, thenat least one of R², R⁴, and R¹¹ is not hydrogen;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

Another aspect of the invention is a method of treating an individualinfected with a bacterium, comprising: administering to the individual acompound selected from the group consisting of the compounds of formulasI, Ia, III, IIIa, IV, IVa, V, and Va.

Another aspect of the invention is a method of treating an individualwith cancer, comprising: administering to the individual a compoundselected from the group consisting of the compounds of formulas I, Ia,III, IIIa, IV, IVa, V, and Va.

Another aspect of the invention is a method of treating cancercomprising the step of contacting a cancer cell with a compound selectedfrom the group consisting of the compounds of formulas I, Ia, III, IIIa,IV, IVa, V, and Va.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In one embodiment, compounds having the structure of formula I areprovided:

wherein R¹ and R² are separately selected, and wherein one of R¹ and R²is a molecular fragment having the structure of formula (II),

Z is selected from the group consisting of O, S, and NR⁵;

R⁶ and R⁷ are separately selected from the group consisting of hydrogen;halogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁-C₂₄ alkyl,C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; arylalkoxy carbonyl; alkoxy carbonylacyl; ester; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; arylalkoxycarbonyl; alkoxy carbonylacyl; ester; amino; aminocarbonyl; amide;aminocarboyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; any bond represented bya dashed and solid line represents a bond selected from the groupconsisting of a single bond and a double bond;

and the remaining substituent of R¹ and R² is selected from the groupconsisting of hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl,ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl;

R³ is ═O;

R^(1′) and R^(2′) are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl, ester;arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

Y is selected from the group consisting of O, S, and NR⁵;

R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, straight C₂₋₆ alkynyl, heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl; or areseparately absent;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

It will be appreciated that when a bond represented by a dashed andsolid line in the compound of formula I is a double bond, somesubstituents on the atoms involved in the double bond will be absentand/or other bonds connected to the atoms will be single bonds so thatthe proper valency of the atoms are not violated. Thus, for example,when the dashed and solid line connected to R¹ is a double bond, R¹′will be absent and the bond between the nitrogen atom and the carbonatom involved in double bonding with R¹ will be a single bond.

In one embodiment, Y and/or Z in the compound of formula I is O. In oneembodiment, R⁴ in the compound of formula I is H. In another embodiment,R⁴ in the compound of formula I is absent, such as to accommodate adouble bond to the nitrogen atom. In some embodiments, R⁸, R⁹, R¹⁰, andR¹¹ are separately hydrogen or are separately absent when necessary toaccommodate double bonds. In some embodiments, R² is a mono-substituted,poly-substituted, or unsubstituted variant of C₁-C₂₄ alkyl. In someembodiments, R⁶ and R⁷ are separately mono-substituted,poly-substituted, or unsubstituted variants of C₁-C₂₄ alkyl.

In one embodiment, the compound of formula I may be subjected to a ringopening reaction to produce the compound of formula Ia:

-   -   (Ia)        where the substituents are as defined above for formula I, with        the proviso that R⁴ is not absent.

In another embodiment, compounds having the structure of formula III areprovided:

wherein Y is selected from the group consisting of O, S, and NR⁵;

R², R⁶, and R⁷ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; arylalkoxycarbonyl; alkoxy carbonylacyl; ester; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl;

R^(2′) is selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; arylalkoxy carbonyl; alkoxy carbonylacyl; ester; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl; or is absent; R⁴ and R⁵ are separatelyselected from the group consisting of hydrogen; mono-substituted,poly-substituted or unsubstituted, straight or branched chain variantsof the following residues: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆ haloalkyl, C₁₋₆ alkoxycarbonyl, andC₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl; —C(O)—C₅₋₆ aryl substituted withC₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆ heteroaryl; C₅₋₆ cycloalkyl; andC₅₋₆ heterocycloalkyl; or are separately absent;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; arylalkoxycarbonyl; alkoxy carbonylacyl; ester; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

It will be appreciated that when a bond represented by a dashed andsolid line in the compound of formula III is a double bond, somesubstituents on the atoms involved in the double bond will be absentand/or other bonds connected to the atoms will be single bonds so thatthe proper valency of the atoms are not violated. Thus, for example,when the dashed and solid line connected to R² is a double bond, R²′will be absent.

In one embodiment, Y is O in the compound of formula III. In oneembodiment, R² in the compound of formula III is a mono-substituted,poly-substituted, or unsubstituted variant of C₁-C₂₄ alkyl. In oneembodiment, R⁶ and R⁷ in the compound of formula III are separatelymono-substituted, poly-substituted, or unsubstituted variants ofstraight chain C₁-C₂₄ alkyl. In one embodiment, R⁴ in the compound offormula III is H. In another embodiment, R⁴ in the compound of formulaIII is absent, such as to accommodate a double bond to the nitrogenatom. In one embodiment R²′ in the compound of formula III is H. Inanother embodiment, R²′ in the compound of formula III is absent, suchas to accommodate a double bond. In some embodiments, R⁸, R⁹, R¹⁰, andR¹¹ are separately hydrogen or are separately absent when necessary toaccommodate double bonds.

In one embodiment, the compound of formula III may be subjected to aring opening reaction to produce the compound of formula IIIa:

where the substituents are as defined above for formula III, with theproviso that R⁴ is not absent.

In another embodiment, a 4-oxazolidinone compound having the structureof formula IV is provided:

wherein R², R⁶, and R⁷ are separately selected from the group consistingof mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl;

R^(2′) is selected from the group consisting of hydrogen andmono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl;

R⁴ is selected from the group consisting of hydrogen, straight- orbranched-chain C₁₋₆ alkyl, straight- or branched-chain C₂₋₆ alkenyl, andstraight- or branched-chain C₂₋₆ alkynyl, or is absent;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bondwith the proviso that such bonds in the compound of formula IV may notboth be double bonds; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

It will be appreciated that when a bond represented by a dashed andsolid line in the compound of formula IV is a double bond, somesubstituents on the atoms involved in the double bond will be absentand/or other bonds connected to the atoms will be single bonds so thatthe proper valency of the atoms are not violated.

In one embodiment, the compound of formula IV may be subjected to a ringopening reaction to produce the compound of formula IVa:

where the substituents are as defined above for formula IV, with theproviso that R⁴ is not absent.

In one embodiment, R² in the compound of formula IV is amono-substituted, poly-substituted, or unsubstituted variant of C₁-C₂₄alkyl. In one embodiment, R⁶ and R⁷ in the compound of formula IV areseparately mono-substituted, poly-substituted, or unsubstituted variantsof straight chain C₁-C₂₄ alkyl. In one embodiment, R⁴ in the compound offormula IV is H. In another embodiment, R⁴ in the compound of formula IVis absent, such as to accommodate a double bond to the nitrogen atom. Inone embodiment R²′ in the compound of formula IV is H. In anotherembodiment, R²′ in the compound of formula IV is absent, such as toaccommodate a double bond.

In another embodiment, compounds having the structure of formula V areprovided:

wherein Y is selected from the group consisting of O, S, and NR⁵;

Z is selected from the group consisting of O, S, and NR⁵;

R², R⁶, and R⁷ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; ester; arylalkoxy carbonyl;amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl;hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; andhalogenated alkyl including polyhalogenated alkyl;

R^(2′) is selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or is absent;

R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl or are separatelyabsent;

R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; ester; arylalkoxycarbonyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro; azido;phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; andhalogenated alkyl including polyhalogenated alkyl; or are separatelyabsent;

R⁶ and R⁸ are optionally bound together to form an optionallysubstituted ring;

any bond represented by a dashed and solid line represents a bondselected from the group consisting of a single bond and a double bond;

any bond represented by a single dashed line is a single bond or isabsent; and

any carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.

In some embodiments, of the compound of formula V, Y is not S. In otherembodiments of the compound of formula V, when R⁶ and R⁸ together forman aryl, at least one of R², R⁴, and R¹¹ is not hydrogen.

It will be appreciated that when a bond represented by a dashed andsolid line in the compound of formula V is a double bond, somesubstituents on the atoms involved in the double bond will be absentand/or other bonds connected to the atoms will be single bonds so thatthe proper valency of the atoms are not violated. Thus, for example,when the dashed and solid line connected to R² is a double bond, R²′will be absent.

In one embodiment, Y is O in the compound of formula V. In oneembodiment, Z is O in the compound of formula V. In one embodiment, R²in the compound of formula V is a mono-substituted, poly-substituted, orunsubstituted variant of C₁-C₂₄ alkyl. In one embodiment, R⁶ and R⁷ inthe compound of formula V are separately mono-substituted,poly-substituted, or unsubstituted variants of straight chain C₁-C₂₄alkyl. In one embodiment, R⁴ in the compound of formula V is H. Inanother embodiment, R⁴ in the compound of formula V is absent, such asto accommodate a double bond to the nitrogen atom. In one embodiment R²′in the compound of formula V is H. In another embodiment, R²′ in thecompound of formula V is absent, such as to accommodate a double bond.In some embodiments, R⁸, R⁹, R¹⁰, and R¹¹ are separately hydrogen or areseparately absent when necessary to accommodate double bonds.

In one embodiment, R⁶ and R⁸ in the compound of formula V are boundtogether to form an optionally substituted aryl. In one such embodiment,the compound of formula V has the structure:

where R², R^(2′), R⁴, R⁷, R¹⁰, and R¹¹ are as defined above.

In one embodiment, the compound of formula V may be subjected to a ringopening reaction to produce the compound of formula Va:

where the substituents are as defined above for formula V, with theproviso that R⁴ is not absent. [0027] In one embodiment, the compound offormulas I, III, IV, or V has the structure of formula VI:

wherein the crossed double bond indicates that the double bond may haveeither a trans or cis geometry.

In another embodiment, the compound of formulas I, III, IV, or V has thestructure formula VII:

wherein the crossed double bond indicates that the double bond may haveeither a trans or cis geometry.

In another embodiment, the compound of formulas I, III, IV, or V has thestructure of formula VIII:

wherein the crossed double bond indicates that the double bond may haveeither a trans or cis geometry.

In some embodiments, tautomers of the compounds of formulas VI, VII, orVIII are provided. For example, the tautomer of the compound of formulaVI having the structure:

is provided.

In one embodiment, the compound of formulas Ia, IIIa, IVa, or Va has thestructure of formula IX:

In some embodiments, prodrugs, metabolites, stereoisomers, andpharmaceutically acceptable salts of the compounds disclosed herein areprovided.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, (ed. H.Bundgaard, Elsevier, 1985), which is hereby incorporated herein byreference in its entirety.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivoyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of pro-drug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); and“Bioreversible Carriers in Drug Design: Theory and Application”, editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providingexamples of esters useful as prodrugs for compounds containing carboxylgroups). Each of the above-mentioned references is herein incorporatedby reference in their entirety.

Metabolites of the compounds disclosed herein include active speciesthat are produced upon introduction of the compounds into the biologicalmilieu.

Where the compounds disclosed herein have at least one chiral center,they may exist as a racemate or as enantiomers. It should be noted thatall such isomers and mixtures thereof are included in the scope of thepresent invention. Furthermore, some of the crystalline forms for thecompounds of disclosed herein may exist as polymorphs. Such polymorphsare included in one embodiment of the present invention. In addition,some of the compounds of the present invention may form solvates withwater (i.e., hydrates) or common organic solvents. Such solvates areincluded in one embodiment of the present invention.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid,phosphoric acid and the like. Pharmaceutical salts can also be obtainedby reacting a compound with an organic acid such as aliphatic oraromatic carboxylic or sulfonic acids, for example acetic, succinic,lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.Pharmaceutical salts can also be obtained by reacting a compound with abase to form a salt such as an ammonium salt, an alkali metal salt, suchas a sodium or a potassium salt, an alkaline earth metal salt, such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, andsalts with amino acids such as arginine, lysine, and the like.

If the manufacture of pharmaceutical formulations involves intimatemixing of the pharmaceutical excipients and the active ingredient in itssalt form, then it may be desirable to use pharmaceutical excipientswhich are non-basic, that is, either acidic or neutral excipients.

In various embodiments, the compounds disclosed herein can be usedalone, in combination with other compounds disclosed herein, or incombination with one or more other agents active in the therapeuticareas described herein.

The term “halogen atom,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

The term “ester” refers to a chemical moiety with formula—(R)_(n)—COOR′, where R and R′ are independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ringcarbon) and heteroalicyclic (bonded through a ring carbon), and where nis 0 or 1.

An “amide” is a chemical moiety with formula —(R)_(n)—C(O)NHR′,—(R)_(n)—NHC(O)R′, —(R)_(n)—C(O)NR′R″, or —(R)_(n)—R′NC(O)R″, where R,R′, and R″ are independently selected from the group consisting ofalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.An amide may be an amino acid or a peptide molecule attached to amolecule of the present invention, thereby forming a prodrug.

Any amine, hydroxy, or carboxyl side chain on the compounds of thepresent invention can be esterified or amidified. The procedures andspecific groups to be used to achieve this end are known to those ofskill in the art and can readily be found in reference sources such asGreene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed.,John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein inits entirety.

The term “aromatic” refers to an aromatic group which has at least onering having a conjugated pi electron system and includes bothcarbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups. The term“carbocyclic” refers to a compound which contains one or more covalentlyclosed ring structures, and that the atoms forming the backbone of thering are all carbon atoms. The term thus distinguishes carbocyclic fromheterocyclic rings in which the ring backbone contains at least one atomwhich is different from carbon. The term “heteroaromatic” refers to anaromatic group which contains at least one heterocyclic ring.

The term “alkyl,” as used herein, means any unbranched or branched,substituted or unsubstituted, saturated hydrocarbon. The alkyl moiety,may be branched, straight chain, or cyclic. The alkyl group may have 1to 20 carbon atoms (whenever it appears herein, a numerical range suchas “1 to 20” refers to each integer in the given range; e.g., “1 to 20carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms,although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated). The alkyl group mayalso be a medium size alkyl having 1 to 10 carbon atoms. The alkyl groupcould also be a lower alkyl having 1 to 5 carbon atoms. The alkyl groupmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from thegroup consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl.

The alkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is(are) one or more group(s) individually andindependently selected from substituted or unsubstituted cycloalkyl,substituted or unsubstituted cylcloalkenyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroaryloxy, heterocyclyl, heterocyclooxy,heteroalicyclyl, hydroxy, substituted or unsubstituted alkoxy,substituted or unsubstituted aryloxy, acyl, thiol, substituted orunsubstituted thioalkoxy, alkylthio, arylthio, cyano, halo, carbonyl,thiocarbonyl, acylalkyl, acylamino, acyloxy, aminoacyl, aminoacyloxy,oxyacylamino, keto, thioketo, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, trihalomethanesulfonyl, and substituted or unsubstituted amino,including mono- and di-substituted amino groups, and the protectedderivatives thereof, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl,propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andthe like. Wherever a substituent is described as being “optionallysubstituted” that substitutent may be substituted with one of the abovesubstituents.

In the present context, the term “cycloalkyl” is intended to coverthree-, four-, five-, six-, seven-, and eight- or more membered ringscomprising carbon atoms only. A cycloalkyl can optionally contain one ormore unsaturated bonds situated in such a way, however, that an aromaticpi-electron system does not arise. Some examples of “cycloalkyl” are thecarbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene,cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene,1,4-cyclohexadiene, cycloheptane, or cycloheptene.

An “alkenyl” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon double bond. An alkenyl may beunbranched or branched, substituted or unsubstituted, unsaturatedhydrocarbon including polyunsaturated hydrocarbons. In some embodiments,the alkenyl is a C₁-C₆ unbranched, mono-unsaturated or di-unsaturated,unsubstituted hydrocarbons. The term “cycloalkenyl” refers to anynon-aromatic hydrocarbon ring, preferably having five to twelve atomscomprising the ring.

An “alkyne” moiety refers to a group consisting of at least two carbonatoms and at least one carbon-carbon triple bond.

The substituent “R”, “R′”, or “R″” appearing by itself and without anumber designation refers to a substituent selected from the groupconsisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclyl (bonded through a ringcarbon).

The term “alkoxy” refers to any unbranched, or branched, substituted orunsubstituted, saturated or unsaturated ether, with C₁-C₆ unbranched,saturated, unsubstituted ethers being preferred, with methoxy beingpreferred, and also, with dimethyl, diethyl, methyl-isobutyl, andmethyl-tert-butyl ethers also being preferred. The term “cycloalkoxy”refers to any non-aromatic hydrocarbon ring, preferably having five totwelve atoms comprising the ring.

An “O-carboxy” group refers to a RC(═O)O— group, where R is as definedherein.

A “C-carboxy” group refers to a —C(═O)OR groups where R is as definedherein.

An “acetyl” group refers to a —C(═O)CH₃, group.

A “trihalomethanesulfonyl” group refers to a X₃CS(═O)₂— group where X isa halogen.

A “cyano” group refers to a —CN group.

An “isocyanato” group refers to a —NCO group.

A “thiocyanato” group refers to a —SCN group.

An “isothiocyanato” group refers to a —NCS group.

A “sulfinyl” group refers to a —S(═O)—R group, with R as defined herein.

A “S-sulfonamido” group refers to a —S(═O)₂NR, group, with R as definedherein.

A “N-sulfonamido” group refers to a RS(═O)₂NH— group with R as definedherein.

A “trihalomethanesulfonamido” group refers to a X₃CS(═O)₂NR— group withX and R as defined herein.

An “O-carbamyl” group refers to a —OC(═O)—NR, group with R as definedherein.

An “N-carbamyl” group refers to a ROC(═O)NH— group, with R as definedherein.

An “O-thiocarbamyl” group refers to a —OC(═S)—NR, group with R asdefined herein.

An “N-thiocarbamyl” group refers to an ROC(═S)NH— group, with R asdefined herein.

A “C-amido” group refers to a —C(═O)—NR₂ group with R as defined herein.

An “N-amido” group refers to a RC(═O)NR′— group, with R and R′ asdefined herein.

The term “perhaloalkyl” refers to an alkyl group where all of thehydrogen atoms are replaced by halogen atoms.

The term “acylalkyl” refers to a RC(═O)R— group, with R as definedherein, and R′ being a diradical alkylene group. Examples of acylalkyl,without limitation, may include CH₃C(═O)CH₂—, CH₃C(═O)CH₂CH₂—,CH₃CH₂C(═O)CH₂CH₂—, CH₃C(═O)CH₂CH₂CH₂—, and the like.

The term “acyloxy” refers to a RC(═O)O— group, with R as defined herein.

The term “alkyloxycarbonyloxy” refers to an alkyl-O—C(═O)O— group.

The term “aryloxycarbonyloxy” refers to an aryl-OC(═O)O— group.

The term “arylalkoxy carbonyl” refers to an aryl-alkoxy(C═O)— group.

The term “aminocarbonyl” refers to an amino(C═O)— group.

The term “aminocarbonyloxy” refers to an amino(C═O)O— group.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substitutent is a groupthat may be substituted with one or more group(s) individually andindependently selected from cycloalkyl, aryl, heteroaryl,heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio,arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino,including mono- and di-substituted amino groups, and the protectedderivatives thereof. The protecting groups that may form the protectivederivatives of the above substituents are known to those of skill in theart and may be found in references such as Greene and Wuts, above.

The term “heterocyclyl” is intended to mean three-, four-, five-, six-,seven-, and eight- or more membered rings wherein carbon atoms togetherwith from 1 to 3 heteroatoms constitute said ring. A heterocyclyl canoptionally contain one or more unsaturated bonds situated in such a way,however, that an aromatic pi-electron system does not arise. Theheteroatoms are independently selected from oxygen, sulfur, andnitrogen.

A heterocyclyl can further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclicthioimides, cyclic carbamates, and the like.

Heterocyclyl rings can optionally also be fused to aryl rings, such thatthe definition includes bicyclic structures. Typically such fusedheterocyclyl groups share one bond with an optionally substitutedbenzene ring. Examples of benzo-fused heterocyclyl groups include, butare not limited to, benzimidazolidinone, tetrahydroquinoline, andmethylenedioxybenzene ring structures.

Some examples of “heterocyclyls” include, but are not limited to,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Binding to the heterocycle can be at the position of aheteroatom or via a carbon atom of the heterocycle, or, for benzo-fusedderivatives, via a carbon of the benzenoid ring.

In the present context the term “aryl” is intended to mean a carbocyclicaromatic ring or ring system. Moreover, the term “aryl” includes fusedring systems wherein at least two aryl rings, or at least one aryl andat least one C₃₋₈-cycloalkyl share at least one chemical bond. Someexamples of “aryl” rings include optionally substituted phenyl,naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl,indenyl, and indanyl. The term “aryl” relates to aromatic, including,for example, benzenoid groups, connected via one of the ring-formingcarbon atoms, and optionally carrying one or more substituents selectedfrom heterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. The aryl group can besubstituted at the para and/or meta positions. In other embodiments, thearyl group can be substituted at the ortho position. Representativeexamples of aryl groups include, but are not limited to, phenyl,3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl,hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl,4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl,4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.

In the present context, the term “heteroaryl” is intended to mean aheterocyclic aromatic group where one or more carbon atoms in anaromatic ring have been replaced with one or more heteroatoms selectedfrom the group comprising nitrogen, sulfur, phosphorous, and oxygen.

Furthermore, in the present context, the term “heteroaryl” comprisesfused ring systems wherein at least one aryl ring and at least oneheteroaryl ring, at least two heteroaryl rings, at least one heteroarylring and at least one heterocyclyl ring, or at least one heteroaryl ringand at least one cycloalkyl ring share at least one chemical bond.

The term “heteroaryl” is understood to relate to aromatic, C₃₋₈ cyclicgroups further containing one oxygen or sulfur atom or up to fournitrogen atoms, or a combination of one oxygen or sulfur atom with up totwo nitrogen atoms, and their substituted as well as benzo- andpyrido-fused derivatives, for example, connected via one of thering-forming carbon atoms. Heteroaryl groups can carry one or moresubstituents, selected from halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, C₁₋₆-alkoxy, C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-aminoalkyl, C₁₋₆-alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments,heteroaryl groups can be five- and six-membered aromatic heterocyclicsystems carrying 0, 1, or 2 substituents, which can be the same as ordifferent from one another, selected from the list above. Representativeexamples of heteroaryl groups include, but are not limited to,unsubstituted and mono- or di-substituted derivatives of furan,benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole,oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole,quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine,furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,triazole, benzotriazole, pteridine, phenoxazole, oxadiazole,benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, andquinoxaline. In some embodiments, the substituents are halo, hydroxy,cyano, O—C₁₋₆-alkyl, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, andamino-C₁₋₆-alkyl.

The terms “purified,” “substantially purified,” and “isolated” as usedherein refer to compounds disclosed herein being free of other,dissimilar compounds with which the compounds of the invention arenormally associated in their natural state, so that the compounds of theinvention comprise at least 0.5%, 1%, 5%, 10%, or 20%, and mostpreferably at least 50% or 75% of the mass, by weight, of a givensample.

Methods of Preparation

Compounds disclosed herein may be obtained by fermentation of a strainof a marine actinomycete a strain isolated from a marine sediment samplecollected at Cocos Lagoon, Guam, a culture of which (also identified as“NPS008920”) was deposited on Jan. 19, 2005 with the American TypeCulture Collection (ATCC) in Rockville, Md. and assigned the ATCC patentdeposition number PTA-6527. The ATCC deposit meets all of therequirements of the Budapest treaty. The culture is also maintained atand available from Nereus Pharmaceutical Culture Collection at 10480Wateridge Circle, San Diego, Calif. 92121. In addition to the specificmicroorganism described herein, it should be understood that mutants,such as those produced by the use of chemical or physical mutagensincluding X-rays, etc. and organisms whose genetic makeup has beenmodified by molecular biology techniques, may also be cultivated toproduce compounds described herein. Compounds produced by this strainmay then be purified.

The production of compounds disclosed herein may be carried out bycultivating the above-identified strain in a suitable nutrient mediumunder conditions described herein, preferably under submerged aerobicconditions, until a substantial amount of compounds are detected in thefermentation; harvesting by extracting the active components from themycelial growth with a suitable solvent; concentrating the solutioncontaining the desired components; then subjecting the concentratedmaterial to chromatographic separation to isolate the compounds fromother metabolites also present in the cultivation medium.

Production of compounds can be achieved at temperature conducive tosatisfactory growth of the producing organism, e.g. from 16 degree C. to40 degree C., but it is preferable to conduct the fermentation at 22degree C. to 32 degree C. The aqueous medium can be incubated for aperiod of time necessary to complete the production of compounds asmonitored by high pressure liquid chromatography (HPLC), preferably fora period of about 2 to 10 days, on a rotary shaker operating at about 50rpm to 300 rpm, preferably at 150 rpm to 250 rpm, for example.

Growth of the microorganisms may be achieved by one of ordinary skill ofthe art by the use of appropriate medium. Broadly, the sources of carboninclude glucose, fructose, mannose, maltose, galactose, mannitol andglycerol, other sugars and sugar alcohols, starches and othercarbohydrates, or carbohydrate derivatives such as dextran, cerelose, aswell as complex nutrients such as oat flour, corn meal, millet, corn,and the like. The exact quantity of the carbon source that is utilizedin the medium will depend in part, upon the other ingredients in themedium, but an amount of carbohydrate between 0.5 to 25 percent byweight of the medium can be satisfactorily used, for example. Thesecarbon sources can be used individually or several such carbon sourcesmay be combined in the same medium, for example. Certain carbon sourcesare preferred as hereinafter set forth.

The sources of nitrogen include amino acids such as glycine, arginine,threonine, methionine and the like, ammonium salt, as well as complexsources such as yeast extracts, corn steep liquors, distiller solubles,soybean meal, cotttonseed meal, fish meal, peptone, and the like. Thevarious sources of nitrogen can be used alone or in combination inamounts ranging from 0.5 to 25 percent by weight of the medium, forexample.

Among the nutrient inorganic salts, which can be incorporated in theculture media, are the customary salts capable of yielding sodium,potassium, magnesium, calcium, phosphate, sulfate, chloride, carbonate,and like ions. Also included are trace metals such as cobalt, manganese,iron, molybdenum, zinc, cadmium, and the like.

Those of skill in the art will recognize many suitable techniques offermentation and purification for use in producing compounds disclosedherein. Compounds obtained in this manner may be further modified togenerate compounds disclosed herein by semi-synthetic routes. Forexample, in some embodiments, compounds of formulas Ia, IIIa, IVa, or Vaare produced by subjecting compounds of formulas I, III, IV, or V to asuitable ring opening reaction such as by adjusting the pH to a suitablelevel (e.g., approximately 7.4).

The compounds disclosed herein may also be synthesized by methodsdescribed below, or by modification of these methods. Ways of modifyingthe methodology include, among others, temperature, solvent, reagentsetc., and will be obvious to those skilled in the art. In general,during any of the processes for preparation of the compounds disclosedherein, it may be necessary and/or desirable to protect sensitive orreactive groups on any of the molecules concerned. This may be achievedby means of conventional protecting groups, such as those described inProtective Groups in Organic Chemistry (ed. J. F. W. McOmie, PlenumPress, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991, which are both hereby incorporated herein byreference in their entirety. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art. Syntheticchemistry transformations useful in synthesizing applicable compoundsare known in the art and include e.g. those described in R. Larock,Comprehensive Organic Transformations, VCH Publishers, 1989, or L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons, 1995, which are both hereby incorporated herein byreference in their entirety.

Compounds described herein can be synthesized by the synthetic scheme A:

In Scheme A, R², R²′, R⁶, R⁷, Y, and Z are as described above forformulas I, III, and IV. R may be hydrogen or a strait or branched chainC₁₋₆ alkyl.

Where the processes for the preparation of the compounds disclosedherein give rise mixtures of stereoisomers, such isomers may beseparated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form orindividual enantiomers may be prepared by stereoselective synthesis orby resolution. The compounds may be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolvedusing a chiral auxiliary by formation of diastereomeric derivatives suchas esters, amides or ketals followed by chromatographic separation andremoval of the chiral auxiliary.

Methods of Use

In some embodiments, the compounds described herein can be used for thetreatment of cancer and/or microbial infection. Thus, for example, thecompounds described herein can be used to treat, prevent the formationof, slow the growth of, or kill cancer cells. In some embodiments, thecompounds described herein are administered to a subject suffering fromcancer. In one embodiment, the subject is a human. In some embodiments,cancer cells are contacted with one or more of the compounds describedherein. In one embodiment, the cancer is a melanoma.

In some embodiments, the compounds described herein can be used to treata bacterial infection. In some embodiments, the compounds prevent theformation of, slow the growth of, or kill bacteria. In some embodiments,the compounds described herein are administered to a subject sufferingfrom a bacterial infection. In one embodiment, the subject is a human.In some embodiments, bacteria are contacted with one or more compoundsdescribed herein. In some embodiments, the bacteria are Gram-positivebacteria. In one embodiment, the bacteria is Staphylococcus aureus(methicillin sensitive), Staphylococcus aureus (methicillin resistant),Streptococcus pneumonia (penicillin sensitive), Streptococcus pneumonia(penicillin resistant), Staphylococcus epidermis (multiple drugresistant), Enterococcus faecalis (vancomycin sensitive), orEnterococcus faecium (vancomycin resistant). In some embodiments, theGram-negative bacteria is Haemophilus influenzae.

Pharmaceutical Compositions

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a physiologically acceptable surface activeagents, carriers, diluents, excipients, smoothing agents, suspensionagents, film forming substances, and coating assistants, or acombination thereof; and a compound disclosed herein. Acceptablecarriers or diluents for therapeutic use are well known in thepharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.(1990), which is incorporated herein by reference in its entirety.Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoringagents, and the like may be provided in the pharmaceutical composition.For example, sodium benzoate, ascorbic acid and esters ofp-hydroxybenzoic acid may be added as preservatives. In addition,antioxidants and suspending agents may be used. In various embodiments,alcohols, esters, sulfated aliphatic alcohols, and the like may be usedas surface active agents; sucrose, glucose, lactose, starch,crystallized cellulose, mannitol, light anhydrous silicate, magnesiumaluminate, magnesium methasilicate aluminate, synthetic aluminumsilicate, calcium carbonate, sodium acid carbonate, calcium hydrogenphosphate, calcium carboxymethyl cellulose, and the like may be used asexcipients; magnesium stearate, talc, hardened oil and the like may beused as smoothing agents; coconut oil, olive oil, sesame oil, peanutoil, soya may be used as suspension agents or lubricants; celluloseacetate phthalate as a derivative of a carbohydrate such as cellulose orsugar, or methylacetate-methacrylate copolymer as a derivative ofpolyvinyl may be used as suspension agents; and plasticizers such asester phthalates and the like may be used as suspension agents.

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to, oral,injection, aerosol, parenteral, and topical administration.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic or organic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

The term “carrier” defines a chemical compound that facilitates theincorporation of a compound into cells or tissues. For example dimethylsulfoxide (DMSO) is a commonly utilized carrier as it facilitates theuptake of many organic compounds into the cells or tissues of anorganism.

The term “diluent” defines chemical compounds diluted in water that willdissolve the compound of interest as well as stabilize the biologicallyactive form of the compound. Salts dissolved in buffered solutions areutilized as diluents in the art. One commonly used buffered solution isphosphate buffered saline because it mimics the salt conditions of humanblood. Since buffer salts can control the pH of a solution at lowconcentrations, a buffered diluent rarely modifies the biologicalactivity of a compound.

The term “physiologically acceptable” defines a carrier or diluent thatdoes not abrogate the biological activity and properties of thecompound.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orsuitable carriers or excipient(s). Techniques for formulation andadministration of the compounds of the instant application may be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., 18th edition, 1990.

Suitable routes of administration may, for example, include oral,rectal, transmucosal, topical, or intestinal administration; parenteraldelivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal, or intraocularinjections. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills, transdermal (including electrotransport) patches, and thelike, for prolonged and/or timed, pulsed administration at apredetermined rate.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or tabletting processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any of the well-knowntechniques, carriers, and excipients may be used as suitable and asunderstood in the art; e.g., in Remington's Pharmaceutical Sciences,above.

Injectables can be prepared in conventional forms, either as liquidsolutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, mannitol, lactose,lecithin, albumin, sodium glutamate, cysteine hydrochloride, and thelike. In addition, if desired, the injectable pharmaceuticalcompositions may contain minor amounts of nontoxic auxiliary substances,such as wetting agents, pH buffering agents, and the like.Physiologically compatible buffers include, but are not limited to,Hanks's solution, Ringer's solution, or physiological saline buffer. Ifdesired, absorption enhancing preparations (for example, liposomes), maybe utilized.

For transmucosal administration, penetrants appropriate to the barrierto be permeated may be used in the formulation.

Pharmaceutical formulations for parenteral administration, e.g., bybolus injection or continuous infusion, include aqueous solutions of theactive compounds in water-soluble form. Additionally, suspensions of theactive compounds may be prepared as appropriate oily injectionsuspensions. Suitable lipophilic solvents or vehicles include fatty oilssuch as sesame oil, or other organic oils such as soybean, grapefruit oralmond oils, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. Aqueous injection suspensions may containsubstances which increase the viscosity of the suspension, such assodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents that increasethe solubility of the compounds to allow for the preparation of highlyconcentrated solutions. Formulations for injection may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compounds with solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate. Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

Further disclosed herein are various pharmaceutical compositions wellknown in the pharmaceutical art for uses that include intraocular,intranasal, and intraauricular delivery. Suitable penetrants for theseuses are generally known in the art. Pharmaceutical compositions forintraocular delivery include aqueous ophthalmic solutions of the activecompounds in water-soluble form, such as eyedrops, or in gellan gum(Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayeret al., Opthalmologica, 210(2):101-3 (1996)); ophthalmic ointments;ophthalmic suspensions, such as microparticulates, drug-containing smallpolymeric particles that are suspended in a liquid carrier medium(Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-solubleformulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)),and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); andocular inserts. All of the above-mentioned references, are incorporatedherein by reference in their entireties. Such suitable pharmaceuticalformulations are most often and preferably formulated to be sterile,isotonic and buffered for stability and comfort. Pharmaceuticalcompositions for intranasal delivery may also include drops and spraysoften prepared to simulate in many respects nasal secretions to ensuremaintenance of normal ciliary action. As disclosed in Remington'sPharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa.(1990), which is incorporated herein by reference in its entirety, andwell-known to those skilled in the art, suitable formulations are mostoften and preferably isotonic, slightly buffered to maintain a pH of 5.5to 6.5, and most often and preferably include antimicrobialpreservatives and appropriate drug stabilizers. Pharmaceuticalformulations for intraauricular delivery include suspensions andointments for topical application in the ear. Common solvents for suchaural formulations include glycerin and water.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For hydrophobic compounds, a suitable pharmaceutical carrier may be acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. A common cosolventsystem used is the VPD co-solvent system, which is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.Naturally, the proportions of a co-solvent system may be variedconsiderably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of POLYSORBATE 80™; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars orpolysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

Agents intended to be administered intracellularly may be administeredusing techniques well known to those of ordinary skill in the art. Forexample, such agents may be encapsulated into liposomes. All moleculespresent in an aqueous solution at the time of liposome formation areincorporated into the aqueous interior. The liposomal contents are bothprotected from the external micro-environment and, because liposomesfuse with cell membranes, are efficiently delivered into the cellcytoplasm. The liposome may be coated with a tissue-specific antibody.The liposomes will be targeted to and taken up selectively by thedesired organ. Alternatively, small hydrophobic organic molecules may bedirectly administered intracellularly.

Additional therapeutic or diagnostic agents may be incorporated into thepharmaceutical compositions. Alternatively or additionally,pharmaceutical compositions may be combined with other compositions thatcontain other therapeutic or diagnostic agents.

Methods of Administration

The compounds or pharmaceutical compositions may be administered to thepatient by any suitable means. Non-limiting examples of methods ofadministration include, among others, (a) administration though oralpathways, which administration includes administration in capsule,tablet, granule, spray, syrup, or other such forms; (b) administrationthrough non-oral pathways such as rectal, vaginal, intraurethral,intraocular, intranasal, or intraauricular, which administrationincludes administration as an aqueous suspension, an oily preparation orthe like or as a drip, spray, suppository, salve, ointment or the like;(c) administration via injection, subcutaneously, intraperitoneally,intravenously, intramuscularly, intradermally, intraorbitally,intracapsularly, intraspinally, intrasternally, or the like, includinginfusion pump delivery; (d) administration locally such as by injectiondirectly in the renal or cardiac area, e.g., by depot implantation; aswell as (e) administration topically; as deemed appropriate by those ofskill in the art for bringing the compound of the invention into contactwith living tissue.

Pharmaceutical compositions suitable for administration includecompositions where the active ingredients are contained in an amounteffective to achieve its intended purpose. The therapeutically effectiveamount of the compounds disclosed herein required as a dose will dependon the route of administration, the type of animal, including human,being treated, and the physical characteristics of the specific animalunder consideration. The dose can be tailored to achieve a desiredeffect, but will depend on such factors as weight, diet, concurrentmedication and other factors which those skilled in the medical artswill recognize. More specifically, a therapeutically effective amountmeans an amount of compound effective to prevent, alleviate orameliorate symptoms of disease or prolong the survival of the subjectbeing treated. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art, especially inlight of the detailed disclosure provided herein.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight and mammalian species treated,the particular compounds employed, and the specific use for which thesecompounds are employed. The determination of effective dosage levels,that is the dosage levels necessary to achieve the desired result, canbe accomplished by one skilled in the art using routine pharmacologicalmethods. Typically, human clinical applications of products arecommenced at lower dosage levels, with dosage level being increaseduntil the desired effect is achieved. Alternatively, acceptable in vitrostudies can be used to establish useful doses and routes ofadministration of the compositions identified by the present methodsusing established pharmacological methods.

In non-human animal studies, applications of potential products arecommenced at higher dosage levels, with dosage being decreased until thedesired effect is no longer achieved or adverse side effects disappear.The dosage may range broadly, depending upon the desired affects and thetherapeutic indication. Typically, dosages may be between about 10microgram/kg and 100 mg/kg body weight, preferably between about 100microgram/kg and 10 mg/kg body weight. Alternatively dosages may bebased and calculated upon the surface area of the patient, as understoodby those of skill in the art.

The exact formulation, route of administration and dosage for thepharmaceutical compositions of the present invention can be chosen bythe individual physician in view of the patient's condition. (See e.g.,Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, whichis hereby incorporated herein by reference in its entirety, withparticular reference to Ch. 1, p. 1). Typically, the dose range of thecomposition administered to the patient can be from about 0.5 to 1000mg/kg of the patient's body weight. The dosage may be a single one or aseries of two or more given in the course of one or more days, as isneeded by the patient. In instances where human dosages for compoundshave been established for at least some condition, the present inventionwill use those same dosages, or dosages that are between about 0.1% and500%, more preferably between about 25% and 250% of the establishedhuman dosage. Where no human dosage is established, as will be the casefor newly-discovered pharmaceutical compounds, a suitable human dosagecan be inferred from ED₅₀ or ID₅₀ values, or other appropriate valuesderived from in vitro or in vivo studies, as qualified by toxicitystudies and efficacy studies in animals.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

Although the exact dosage will be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.1 mg and 2000 mg of each active ingredient,preferably between 1 mg and 500 mg, e.g. 5 to 200 mg. In otherembodiments, an intravenous, subcutaneous, or intramuscular dose of eachactive ingredient of between 0.01 mg and 100 mg, preferably between 0.1mg and 60 mg, e.g. 1 to 40 mg is used. In cases of administration of apharmaceutically acceptable salt, dosages may be calculated as the freebase. In some embodiments, the composition is administered 1 to 4 timesper day. Alternatively the compositions of the invention may beadministered by continuous intravenous infusion, preferably at a dose ofeach active ingredient up to 1000 mg per day. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections. In some embodiments, the compounds will be administered fora period of continuous therapy, for example for a week or more, or formonths or years.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%.

In cases of local administration or selective uptake, the effectivelocal concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. Recognized in vitro models exist for nearly every class ofcondition, including but not limited to cancer, cardiovascular disease,and various immune dysfunction. Similarly, acceptable animal models maybe used to establish efficacy of chemicals to treat such conditions.When selecting a model to determine efficacy, the skilled artisan can beguided by the state of the art to choose an appropriate model, dose, androute of administration, and regime. Of course, human clinical trialscan also be used to determine the efficacy of a compound in humans.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions comprising a compound of theinvention formulated in a compatible pharmaceutical carrier may also beprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

EXAMPLES Example 1 Fermentation of NPS-008920

Strain NPS008920 was grown in a 40 ml tube containing 10 ml of seedmedium consisting of the following per liter of sea water: starch, 10 g;yeast extract, 4 g; and peptone, 2 g. The culture was allowed toincubate for 3 days at 28 degree C. on a rotary shaker operating at 250rpm. The vegetative culture was mixed with 2 ml of cryoprotectivesolution consisting of 500 g glycerol per liter of deionized water. 1.5ml portions of this mixture were transferred to sterile cryogenic tube(1.8 ml capacity). The vegetative cultures so obtained were frozen andstored at −80 degree C.

Seed culture was prepared by transferring two 1.5 ml of thecryopreservative cultures to a 100 ml flask containing 100 ml of sterileseed medium having the same composition as the above. The seed culturewas incubated at 28 degrees C. for 4 days on a rotary shaker operatingat 250 rpm. Five ml of this seed culture was inoculated into nine 500 mlflasks each containing 100 ml of the seed medium. The second seedcultures were incubated at 28 degrees C. for 2 days on a rotary shakeroperating at 250 rpm. Five to six ml each of the second seed culture wasinoculated into the production medium having the same composition of theseed medium. The production culture was incubated at 28 degree C. for 5days on a rotary shaker operating at 250 rpm. The culture broth (5 L)was extracted with 5 liters of ethyl acetate. The extract was dried invacuo.

Example 2 Purification to Obtain Compounds of Formulae VI and VII

The crude extract (0.38 g) of NPS008920 obtained as described in Example1 was dissolved in MeOH (19 ml) and injected in 950 μl aliquots (19 mgeach) on preparative reversed phase HPLC using the following conditions:

-   -   Column: Ace 5 um C18-HL    -   Dimensions: 15 cm×21 mm ID    -   Flow rate: 14.5 ml/min    -   Detection: UV DAD    -   Solvent: 20% ACN/H₂O to 80% ACN/H₂O in 12 min; 80% to 100%        ACN/H₂O in 1 min then 9 min at 100% ACN

Two compounds were well separated using the above conditions. Onecompound (identified as the compound of formula VI) eluted at 21minutes. The second compound (identified as the compound of formula VII)eluted at 23 minutes. These compounds were further purified by reversedphase semi-preparative HPLC using the following conditions:

-   -   Column: Hamilton 10 um PRP-1 (Polymeric Reversed Phase)    -   Dimensions: 25 cm×10 mm ID    -   Flow rate: 3 ml/min    -   Detection: UV DAD    -   Solvent: Gradient of 40% ACN/H₂O to 80% ACN/H₂O in 8 min; 80% to        100% ACN in 1 min then 15 min at 100% ACN.

Example 3 Fermentation of NPS-008920

Strain NPS008920 was grown in a 100 ml flask containing 100 ml of seedmedium consisting of the following per liter of sea water: starch, 10 g;yeast extract, 4 g; and peptone, 2 g. The culture was allowed toincubate for 6 days at 28 degree C. on a rotary shaker operating at 250rpm. The vegetative culture was mixed with cryoprotective solutionconsisting of 500 g glycerol per liter of deionized water to yield afinal glycerol concentration of 10%. 1.5 ml portions of this mixturewere transferred to sterile cryogenic tube (1.8 ml capacity). Thevegetative cultures so obtained were frozen and stored at −80 degree C.

Seed culture was prepared by transferring two 1.5 ml of thecryopreservative cultures to a 100 ml flask containing 100 ml of sterileseed medium having the same composition as the above. The seed culturewas incubated at 28 degrees C. for 3 days on a rotary shaker operatingat 250 rpm. Five ml of this seed culture was inoculated into nine 500 mlflasks each containing 100 ml of the seed medium. The second seedcultures were incubated at 28 degrees C. for 2 days on a rotary shakeroperating at 250 rpm. Five to six ml each of the second seed culture wasinoculated into the production medium having the same composition of theseed medium. The production culture was incubated at 28 degree C. for 5days on a rotary shaker operating at 250 rpm. The culture broth (10 L)was extracted with 10 liters of ethyl acetate. The extract was dried invacuo.

Example 4 Purification to Obtain the Compound of Formula VIII

The crude extract (1.2 g) of NPS008920 obtained as described in Example3 was dissolved in water (100 mL) and extracted with hexane (3×100 mL).The combined organic layer was concentrated to yield about 570 mg ofFormula VI enriched material which was purified by preparative scalereversed phase HPLC using the following conditions (50 mg perinjection).

-   -   Column: Ace 5 um C18-HL

Dimensions: 15 cm×21 mm ID

-   -   Flow rate: 14.5 ml/min    -   Detection: UV DAD    -   Solvent: 50% ACN/H₂O to 100% ACN in 12 min; then 13 min at 100%        ACN

The compound of formula VIII eluted at about 18 min as a minor compound.This compound was further purified by reversed phase preparative HPLCusing the following conditions with different solvent system:

-   -   Column: Ace 5 um C18-HL    -   Dimensions: 15 cm×21 mm ID    -   Flow rate: 14.5 ml/min    -   Detection: UV DAD    -   Solvent: 20% MeOH/H₂O to 80% MeOH/H₂O in 12 min; 80% to 100%        MeOH/H₂O in 1 min then 9 min at 100% MeOH

The pure compound of formula VIII was eluted at about 18.5 min.

Example 5 Preparation of the Compound of Formula IX

The compound of formula IX was obtained by adding pH 7.4 buffer (2 mL)into a solution of the compound of formula XIII (4.2 mg) in acetonitrileand letting it stand at room temperature for about 4 days. Theacetonitrile was removed by rotavap and the remaining aqueous layer wasextracted with methyle chloride (3×20 mL). The combined organic layerwas concentrated to yield the compound of formula IX (3.2 mg).

Example 6 Structural Characterization

The compounds of Formulas VI, VII, VIII, and IX were characterized asfollows:

Formula VI: [α]^(21.2) _(D)−30.99 (c 0.0002, MeOH); UV (MeOH) λ_(max)310 (ε 22,700), 253 (9,100) nm; UV (Acetonitrile/H₂O) λ_(max) 310, 255nm. HRESIMS m/z 322.2372 [M+H] Δ_(calc) C₁₉H₃₂NO₃ (322.2382)=3.3 ppm.

Formula VII: UV (Acetonitrile/H₂O) λ_(max) 310, 255 nm. HRESIMS m/z336.2527 [M+H] Δ_(calc) C₂₀H₃₄NO₃ (336.2539)=3.5 ppm.

Formula VIII: UV (Acetonitrile/H₂O) λ_(max) 310, 255 nm. HRESIMS m/z308.2234 [M+H] Δ_(calc) C₁₈H₃₀NO₃ (308.2226)=2.8 ppm.

Formula IX: UV (Acetonitrile/H₂O) λ_(max) 245 nm. LRESIMS m/z 340 [M+H].

¹H-NMR and ¹³C-NMR was conducted in order to elucidate the structures ofthe four compounds. The results are indicated in Tables 1-4 and theassignments were made as illustrated in the following structures:

The double bond geometry of C-1′ to C-2 was not established for FormulaeVI, VII and VIII.

TABLE 1 ¹H NMR Assignments. Formula VII Formula VI CDCl₃ DMSO-d6 CDCl₃**δ_(H) int., Pos *δ_(H) int., mult, J (Hz) **δ_(H) int., mult, J (Hz)mult, J (Hz)  5 4.88 1H, dd, 4.7, 6.6 4.59 1H, dd, 4.4, 7.0 4.58 1H, dd,4.4, 7.0  1′ 5.28 1H, s 5.18 1H, s 5.17 1H, s  3′ 5.98 1H, br s 5.87 1H,br s 5.86 1H, br s  5′ 2.08 2H, br t, 7.5 2.10 3H, br t, 7.6 2.09 2H, brt, 7.6  6′ 1.43 2H, m 1.44 2H, m 1.44 2H, m  7′ 1.25 2H, ca 1.26 2H, m1.26 2H, m  8′ 1.25 2H, ca 1.26 2H, m 1.26 2H, m  9′ 1.25 2H, ca 1.232H, m 1.23 2H, m 10′ 1.28 2H, ca 1.26 2H, m 1.26 2H, m 11′ 0.86 3H, t,6.6 0.87 3H, t, 7.0 0.85 3H, t, 7.0 12′ 2.11 3H, br s 2.15 3H, br s 2.143H, br s  1″ 1.71 1H, m 1.79 1H, m 1.77 1H, m 1.84 1H, m 1.96 1H, m 1.941H, m  2″ 1.31 2H, ca 1.40 2H, m 1.42 2H, m  3″ 1.30 2H, ca 1.36 2H, m1.28 2H, m  4″ 0.87 3H, t, 6.6 0.90 3H, t, 7.0 1.28 2H, m  5″ — — 0.863H, t, 7.0 *δ_(H) values referenced to internal solvent for DMSO-d₆ at2.50 ppm **δ_(H) values referenced to internal solvent for CDCl₃ at 7.24ppm

TABLE 2 ¹H NMR Assignments. Formula VIII Formula IX CDCl₃ CDCl₃ Pos*δ_(H) int., mult, J (Hz) *δ_(H) int., mult, J (Hz)  5 4.59 1H, dd, 4.4,7.0 5.24 1H, dd, 3.8, 8.5  1′ 5.18 1H, s 3.56 1H, d, 16.4 3.67 1H, d,16.4  3′ 5.87 1H, br s 6.02 1H, br s  5′ 2.10 3H, br t, 7.6 2.15 2H, brt, 7.6  6′ 1.44 2H, m 1.46 2H, m  7′ 1.28 2H, m 1.26 2H, m  8′ 1.24 2H,m 1.26 2H, m  9′ 1.27 2H, m 1.23 2H, m 10′ 0.86 3H, t, 7.0 1.26 2H, m11′ — 0.87 3H, t, 7.0 12′ 2.15 3H, br s 2.15 3H, br s  1″ 1.79 1H, m1.82 1H, m 1.96 1H, m 1.96 1H, m  2″ 1.41 2H, m 1.34 2H, m  3″ 1.35 2H,m 1.31 2H, m  4″ 0.90 3H, t, 7.0 0.88 3H, t, 7.0 *δ_(H) valuesreferenced to internal solvent for CDCl₃ at 7.24 ppm

TABLE 3 ¹³C NMR Assignments. Formula VI Formula VII δ_(C)* mult inδ_(C)** mult in δ_(C)** mult in Pos DMSO CDCl₃ CDCl₃  2 165.3 s 166.7 s166.5 s  4 173.8 s 173.7 s 173.6 s  5  77.6 d  78.6 d  78.6 d  1′  83.6d  84.0 d  84.0 d  2′ 187.9 s 189.4 s 189.4 s  3′ 124.6 d 124.3 d 124.3d  4′ 155.4 s 157.7 s 157.7 s  5′  40.4 t  41.5 t  41.4 t  6′  27.0 t 27.6 t  27.6 t  7′  28.4 t  29.1 t^(e)  29.1 t^(d)  8′  28.6 t  29.2t^(e)  29.7 t^(d)  9′  31.1 t  31.8 t  31.7 t 10′  22.0 t  22.6 t  22.6t 11′  13.9 q  14.1 q  14.0 q 12′  18.4 q  19.2 q  19.1 q  1″  29.9 t 30.8 t  31.0 t  2″  25.6 t  26.2 t  23.7 t  3″  21.6 t  22.2 t  31.2 t 4″  13.6 q  13.7 t  22.3 t  5″ — —  13.9 q *δ_(C) values referenced tointernal solvent for DMSO-d₆ at 39.50 ppm **δ_(C) values referenced tointernal solvent for CDCl₃ at 77.00 ppm (some values obtained throughHMBC and HMQC) ^(d,e)may be interchangeable

TABLE 4 ¹³C NMR Assignments. Formula VIII Formula IX δ_(C)** mult inδ_(C)** mult in Pos CDCl₃ CDCl₃  2 166.6 s 166.6 s  4 173.7 s 172.8 s  5 78.6 d  74.3 d  1′  84.1 d  50.3 t  2′ 189.4 s 193.5 s  3′ 124.3 d121.5 d  4′ 157.7 s 164.9 s  5′  41.5 t  41.5 t  6′  27.6 t  27.5 t  7′ 28.9 t  29.0 t^(a)  8′  31.7 t  29.2 t^(a)  9′  22.5 t  31.7 t 10′ 14.0 q  22.6 t 11′ —  14.0 q^(b) 12′  19.1 q  20.0 q  1″  30.8 t  31.2t  2″  26.1 t  27.2 t  3″  22.2 t  22.3 t  4″  13.7 q  13.9 q^(b)**δ_(C) values referenced to internal solvent for CDCl₃ at 77.00 ppm^(a,b)may be interchangeable

Example 7 Growth Inhibition of Murine Melanoma B16-F10 Cells

B16-F10 (ATCC; CRL-6475) a murine melanoma cell line was maintained incomplete Dulbecco's Modification of Eagle's Medium (DMEM) (DMEMsupplemented with 10% (v/v) Fetal bovine serum, 2 mM glutamine, 10 mMHEPES and Penicillin/Streptomycin at 100 IU/ml and 100 μg/mlrespectively). The cells were cultured in an incubator at 37° C. in 5%CO₂ and 95% humidified air.

For cell growth inhibition assays, B16-F10 cells were seeded at 1.25×10³cells/well in 90 μl complete media into Corning 3904 black-walled,clear-bottom tissue culture plates and the plates were incubatedovernight to allow cells to establish and enter log phase growth. 20 mMstock solutions of formula VI were prepared in 100% DMSO. 10×concentrated serial dilutions of formula VI were prepared in completemedia. Ten μl volumes of the serial dilutions were added to the testwells in triplicate resulting in final concentrations ranging from 20 μMto 6.32 nM. The plates were returned to the incubator for 48 hours. Thefinal concentration of DMSO was 0.25% in all samples.

Following 48 hours of drug exposure, 10 μl of 0.2 mg/ml resazurin(obtained from Sigma-Aldrich Chemical Co.) in Mg²⁺, Ca²⁺ free phosphatebuffered saline was added to each well and the plates were returned tothe incubator for 3-6 hours. Since living cells metabolize Resazurin,the fluorescence of the reduction product of Resazurin was measuredusing a Fusion microplate fluorometer (Packard Bioscience) withλ_(ex)=535 nm and λ_(em)=590 nm filters. Resazurin dye in medium withoutcells was used to determine the background, which was subtracted fromthe data for all experimental wells. The data were normalized to theaverage fluorescence of the cells treated with media+0.25% DMSO (100%cell growth) and EC₅₀ values (the drug concentration at which 50% of themaximal observed growth inhibition is established) were determined usinga standard sigmoidal dose response curve fitting algorithm (XLfit 3.0,ID Business Solutions Ltd).

The data in Table 5 summarize the mean growth inhibitory effects of thecompound of formula VI against the murine melanoma, B16-F10 cell line.

TABLE 5 EC₅₀ values of formula V against B16-F10 cells. FORMULA VIB16-F10 EC₅₀ (μM) 6.0 ± 2.6* *data presented as mean ± standarddeviation of three independent experiments

The EC₅₀ value indicates that the compound of formula VI inhibits thegrowth of B16-F10 tumor cells.

Example 8 Antimicrobial Assays

Minimum inhibitory concentrations (MICs) were determined according tothe National Committee for Clinical Laboratory Standards (NCCLS)susceptibility test guideline M7-A5 (Ferraro, M. 2001 Methods forDilution Antimicrobial Susceptibility Tests for Bacteria that GrowAerobically; Approved Standard (NCCLS). National Committee for ClinicalLaboratory Standards (NCCLS), Villanova, which is incorporated herein byreference in its entirety). The compound of formula VI was tested inDMSO while the compound of formula VII was tested in aqueous MeOH.Antimicrobial data for the compounds of formulae VI and VII are shown inTable 6. The compound of formulae VIII and IX were tested in DMSO.Antimicrobial data for the compounds of formulae VIII and IX are shownin Table 7.

TABLE 6 Antimicrobial data. MIC (μg/ml) Organism Formula VI Formula VIIStaphylococcus aureus - MSSA 0.88 6 Staphylococcus aureus - MRSA 1.041.5 S. epi. 700578 0.54 1.25 S. epi. 700582 0.54 0.75 PSSP 2.58 8 PRSP4.67 6 VSE 3.67 3 VRE 1.83 1.5 E. c. imp >32 >32 E. c. MCR106 >32 >32 E.c. 25922 >32 >32 H. inf. 49247 12 12 H. inf. 49766 12 16 Candidaalbicans >32 >32

TABLE 7 Antimicrobial data. MIC (μg/ml) Organism Formula VIII Formula IXStaphylococcus aureus - MSSA 4 24 Staphylococcus aureus - MRSA 3 >32PSSP 10 >32 H. inf. 49247 16 >32 H. inf. 49766 5 >32

The compounds of formulas VI, VII, and VIII were shown to possessanti-bacterial activity versus the Gram-positive microorganisms testedand were also weakly active against the Gram-negative microorganismHaemophilus influenzae.

1. A compound having the structure of formula I or Ia:

and pharmaceutically acceptable salts or prodrugs thereof, wherein: R¹and R² are separately selected, wherein one of R¹ and R² is a molecularfragment having the structure of formula (II),

Z is selected from the group consisting of O, S, and NR⁵; R⁶ and R⁷ areseparately selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; R⁸ and R⁹are separately selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; andhalogenated alkyl including polyhalogenated alkyl; or are separatelyabsent; R¹⁰ and R¹¹ are separately selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl; ester;arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; and the remainingsubstituent of R¹ and R² is selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; heteroaryl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; andhalogenated alkyl including polyhalogenated alkyl; R³ is ═O; R^(1′) isselected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; or areseparately absent; R^(2′) is selected from the group consisting ofhydrogen; halogen; mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy;alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl; cycloalkenyl;alkoxy; cycloalkoxy; heteroaryl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy; cyano; andhalogenated alkyl including polyhalogenated alkyl; or are separatelyabsent; Y is separately selected from the group consisting of O, S, andNR⁵; R⁴ and each R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl, or areseparately absent, provided that R⁴ is not absent in a compound offormula Ia; any bond represented by a dashed and solid line represents abond selected from the group consisting of a single bond and a doublebond; any bond represented by a single dashed line is a single bond oris absent; and any carbon-carbon double bond has a configurationselected from the group consisting of cis and trans.
 2. The compound ofclaim 1, wherein Y is O.
 3. The compound of claim 1, wherein Z is O. 4.The compound of claim 1, wherein R⁴ is H.
 5. The compound of claim 1,wherein R⁴ is absent.
 6. The compound of claim 1, wherein R⁸, R⁹, R¹⁰,and R¹¹ are separately hydrogen or absent.
 7. The compound of claim 1,wherein R² is a mono-substituted, poly-substituted, or unsubstitutedvariant of C₁-C₂₄ alkyl.
 8. The compound of claim 1, wherein R⁶ and R⁷are separately mono-substituted, poly-substituted, or unsubstitutedvariants of C₁-C₂₄ alkyl.
 9. A compound having the structure of formulaIII or IIIa:

and pharmaceutically acceptable salts or prodrugs thereof, wherein: Y isselected from the group consisting of O, S, and NR⁵; R², R⁶, and R⁷ areseparately selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; R^(2′) isselected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; or isabsent; R⁴ and R⁵ are separately selected from the group consisting ofhydrogen; mono-substituted, poly-substituted or unsubstituted, straightor branched chain variants of the following residues: C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₂₋₆ heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆haloalkyl, C₁₋₆ alkoxycarbonyl, and C₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl;—C(O)—C₅₋₆ aryl substituted with C₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆heteroaryl; C₅₋₆ cycloalkyl; and C₅₋₆ heterocycloalkyl or are separatelyabsent, provided that R⁴ is not absent in a compound of formula IIIa;R⁸, R⁹, R¹⁰, and R¹¹ are separately selected from the group consistingof hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; alkoxy carbonylacyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; any bond represented bya dashed and solid line represents a bond selected from the groupconsisting of a single bond and a double bond; any bond represented by asingle dashed line is a single bond or is absent; and any carbon-carbondouble bond has a configuration selected from the group consisting ofcis and trans.
 10. The compound of claim 9, wherein Y is O.
 11. Thecompound of claim 9, wherein R² is a mono-substituted, poly-substituted,or unsubstituted variant of C₁-C₂₄ alkyl.
 12. The compound of claim 9,wherein R⁶ and R⁷ are separately mono-substituted, poly-substituted, orunsubstituted variants of straight chain C₁-C₂₄ alkyl.
 13. The compoundof claim 9, wherein R⁴ is H.
 14. The compound of claim 9, wherein R⁴ isabsent.
 15. The compound of claim 9, wherein R²′ is H.
 16. The compoundof claim 9, wherein R²′ is absent.
 17. The compound of claim 9, whereinR⁸, R⁹, R¹⁰, and R¹¹ are separately hydrogen or absent.
 18. A compoundhaving the structure of formula IV or IVa:

and pharmaceutically acceptable salts or prodrugs thereof, wherein: R²,R⁶, and R⁷ are separately selected from the group consisting ofmono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; R^(2′) is selected from the group consistingof hydrogen and mono-substituted, poly-substituted or unsubstituted,straight or branched chain variants of the following residues: C₁-C₂₄alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; R⁴ is selected from the groupconsisting of hydrogen, straight- or branched-chain C₁₋₆ alkyl,straight- or branched-chain C₂₋₆ alkenyl, and straight- orbranched-chain C₂₋₆ alkynyl, or is absent, provided that R⁴ is notabsent in a compound of formula IVa; any bond represented by a dashedand solid line represents a bond selected from the group consisting of asingle bond and a double bond with the proviso that such bonds in thecompound of formula IV may not both be double bonds; and anycarbon-carbon double bond has a configuration selected from the groupconsisting of cis and trans.
 19. A compound having the structure offormula V or Va:

and pharmaceutically acceptable salts or prodrugs thereof, wherein: Y isselected from the group consisting of O and NR⁵; Z is selected from thegroup consisting of O, S, and NR⁵; R², R⁷, and R⁶ are separatelyselected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl; R^(2′) is selected from the groupconsisting of hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or is absent; R⁴ and each R⁵ are separatelyselected from the group consisting of hydrogen; mono-substituted,poly-substituted or unsubstituted, straight or branched chain variantsof the following residues: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆ haloalkyl, C₁₋₆ alkoxycarbonyl, andC₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl; —C(O)—C₅₋₆ aryl substituted withC₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆ heteroaryl; C₅₋₆ cycloalkyl; andC₅₋₆ heterocycloalkyl or are separately absent, provided that R⁴ is notabsent in a compound of formula Va; R⁸ and R⁹ are separately selectedfrom the group consisting of hydrogen; halogen; mono-substituted,poly-substituted or unsubstituted, straight or branched chain variantsof the following residues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy;cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; R¹⁰ and R¹¹ areseparately selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; or areseparately absent; R⁶ and R⁸ are optionally bound together to form anoptionally substituted ring; any bond represented by a dashed and solidline represents a bond selected from the group consisting of a singlebond and a double bond; any bond represented by a single dashed line isa single bond or is absent; and any carbon-carbon double bond has aconfiguration selected from the group consisting of cis and trans. 20.The compound of claim 19, having the structure:


21. A compound having the structure of formula V or Va:

and pharmaceutically acceptable salts or prodrugs thereof, wherein: Y isselected from the group consisting of O, S, and NR⁵; Z is selected fromthe group consisting of O, S, and NR⁵; R², R⁶, and R⁷ are separatelyselected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; amino;aminocarbonyl; amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy;alkylthio; arylthio; oxysulfonyl; carboxy; cyano; and halogenated alkylincluding polyhalogenated alkyl; R^(2′) is selected from the groupconsisting of hydrogen; halogen; mono-substituted, poly-substituted orunsubstituted, straight or branched chain variants of the followingresidues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄ alkynyl; acyl;acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy; cycloalkyl;cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl; heterocycloalkyl;ester; arylalkoxy carbonyl; amino; aminocarbonyl; amide;aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio; arylthio;oxysulfonyl; carboxy; cyano; and halogenated alkyl includingpolyhalogenated alkyl; or is absent; R⁴ and each R⁵ are separatelyselected from the group consisting of hydrogen; mono-substituted,poly-substituted or unsubstituted, straight or branched chain variantsof the following residues: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆heteroalkyl, C₂₋₆ aminoalkyl, C₂₋₆ haloalkyl, C₁₋₆ alkoxycarbonyl, andC₂₋₆ hydroxyalkyl; C₃₋₈ cycloalkyl; —C(O)—C₅₋₆ aryl substituted withC₁₋₃ alkyl or halo; C₅₋₆ aryl; C₅₋₆ heteroaryl; C₅₋₆ cycloalkyl; andC₅₋₆ heterocycloalkyl or are separately absent, provided that R⁴ is notabsent in a compound of formula Va; R⁸ and R⁹ are separately selectedfrom the group consisting of hydrogen; halogen; mono-substituted,poly-substituted or unsubstituted, straight or branched chain variantsof the following residues: C₁-C₂₄ alkyl, C₂-C₂₄ alkenyl, or C₂-C₂₄alkynyl; acyl; acyloxy; alkyloxycarbonyloxy; aryloxycarbonyloxy;cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl; heteroaryl;heterocycloalkyl; ester; arylalkoxy carbonyl; amino; aminocarbonyl;amide; aminocarbonyloxy; nitro; azido; phenyl; hydroxy; alkylthio;arylthio; oxysulfonyl; carboxy; and halogenated alkyl includingpolyhalogenated alkyl; or are separately absent; R¹⁰ and R¹¹ areseparately selected from the group consisting of hydrogen; halogen;mono-substituted, poly-substituted or unsubstituted, straight orbranched chain variants of the following residues: C₁-C₂₄ alkyl, C₂-C₂₄alkenyl, or C₂-C₂₄ alkynyl; acyl; acyloxy; alkyloxycarbonyloxy;aryloxycarbonyloxy; cycloalkyl; cycloalkenyl; alkoxy; cycloalkoxy; aryl;heteroaryl; heterocycloalkyl; ester; arylalkoxy carbonyl; alkoxycarbonylacyl; amino; aminocarbonyl; amide; aminocarbonyloxy; nitro;azido; phenyl; hydroxy; alkylthio; arylthio; oxysulfonyl; carboxy;cyano; and halogenated alkyl including polyhalogenated alkyl; or areseparately absent; R⁶ and R⁸ are optionally bound together to form anoptionally substituted ring, provided that if R⁶ and R⁸ together form anaryl, then at least one of R², R⁴, and R¹¹ is not hydrogen; any bondrepresented by a dashed and solid line represents a bond selected fromthe group consisting of a single bond and a double bond; any bondrepresented by a single dashed line is a single bond or is absent; andany carbon-carbon double bond has a configuration selected from thegroup consisting of cis and trans.
 22. The compound of claim 21, havingthe structure:


23. A pharmaceutical composition, comprising a compound of claim 1 and aphysiologically acceptable surface active agent, carrier, diluent,excipient, smoothing agent, suspension agent, film forming substance, orcoating assistant, or a combination thereof.
 24. A pharmaceuticalcomposition, comprising a compound of claim 9 and a physiologicallyacceptable surface active agent, carrier, diluent, excipient, smoothingagent, suspension agent, film forming substance, or coating assistant,or a combination thereof.
 25. A pharmaceutical composition, comprising acompound of claim 18 and a physiologically acceptable surface activeagent, carrier, diluent, excipient, smoothing agent, suspension agent,film forming substance, or coating assistant, or a combination thereof.26. A pharmaceutical composition, comprising a compound of claim 19 anda physiologically acceptable surface active agent, carrier, diluent,excipient, smoothing agent, suspension agent, film forming substance, orcoating assistant, or a combination thereof.
 27. A pharmaceuticalcomposition, comprising a compound of claim 21 and a physiologicallyacceptable surface active agent, carrier, diluent, excipient, smoothingagent, suspension agent, film forming substance, or coating assistant,or a combination thereof.
 28. A pharmaceutical composition, comprising acompound having the structure of formula VI, VII, VIII, or IX:

and a physiologically acceptable surface active agent, carrier, diluent,excipient, smoothing agent, suspension agent, film forming substance, orcoating assistant, or a combination thereof.